Complement, C1q, and C1q-Related Molecules Regulate Macrophage Polarization

Abstract

Complement is a critical system of enzymes, regulatory proteins, and receptors that regulates both innate and adaptive immune responses. Natural mutations in complement molecules highlight their requirement in regulation of a variety of human conditions including infectious disease and autoimmunity. As sentinels of the immune system, macrophages are specialized to respond to infectious microbes, as well as normal and altered self, and dictate appropriate immune responses. Complement components such as anaphylatoxins (C3a and C5a) and opsonins [C3b, C1q, mannan binding lectin (MBL)] influence macrophage responses. While anaphylatoxins C3a and C5a trigger inflammasome activation, opsonins such as C1q and related molecules (MBL and adiponectin) downregulate inflammasome activation and inflammation, and upregulate engulfment of apoptotic cells consistent with a pro-resolving or M2 macrophage phenotype. This review summarizes our current understanding of the influence of the complement system on macrophage polarization with an emphasis on C1q and related molecules.

Complement in disease: a defence system turning offensive

“…Complement activation products, particularly C3a and C5a, can modulate the activation state of most immune cell types, including neutrophils, monocytes, macrophages, and dendritic cells 19,36,37 (FIG. 2).…”

“…Activation of macrophages by C1q or iC3b induces the production of IL-10 and their participation in the clearance of apoptotic cells and damaged molecules — physiologic mechanisms that are not associated with an inflammatory process. Conversely, macrophage stimulation with C3a, C5a or C5b–9 usually induces a proinflammatory phenotype with the production of iNOS, TNF, and IL-1β driving pathogen elimination 37 . Similarly, engagement of C3aR or C5aR1 on dendritic cells is associated with their activation via PI3K/AKT, ERK, and NF-κB signalling, whereas C1q supports the differentiation of monocytes toward dendritic cells by engaging the leukocyte-associated immunoglobulin-like receptor 1 (REFS 43,44).…”

Cell Surface CD36 Protein in Monocyte/Macrophage Contributes to Phagocytosis during the Resolution Phase of Ischemic Stroke in Mice

“…Phagocytosis-Phagocytosis is a salient feature of alternatively activated M2 macrophages (27,28). CD36 and LAL are crucial for fatty acid oxidation, which is required for M2 macrophage polarization (29).…”

Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice

“…C5aR expression is induced in proliferating hepatocytes or in response to inflammatory cytokines (Qin and Gao 2006). Macrophages also express complement receptor (CR) 1, CR3 (CD11b) and CR4 (CD11c), with CR1 binding to C1q, C3b and C4b, all associated with opsonization of cells and particles (Bohlson et al 2014). Interestingly, C1q is suggested to shift macrophage polarization from the inflammatory M1 phenotype to a pro-resolution M2 phenotype, highly poised for phagocytosis (Bohlson et al 2014).…”